Shinoda Yo, Ehara Shunsuke, Tatsumi Satoshi, Yoshida Eiko, Takahashi Tsutomu, Eto Komyo, Kaji Toshiyuki, Fujiwara Yasuyuki
Department of Environmental Health, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.
Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science.
J Toxicol Sci. 2019;44(3):191-199. doi: 10.2131/jts.44.191.
Exposure to organic mercury, especially methylmercury (MeHg), causes Minamata disease, a severe chronic neurological disorder. Minamata disease predominantly affects the central nervous system, and therefore, studies on the mechanisms of MeHg neurotoxicity have focused primarily on the brain. Although the peripheral nervous system is also affected by the organometallic compound and shows signs of neural degeneration, the mechanisms of peripheral MeHg neurotoxicity remain unclear. In the present study, we performed quantitative immunohistochemical analyses of the dorsal root ganglion (DRG) and associated sensory and motor fibers to clarify the mechanisms of MeHg-induced peripheral neurotoxicity in Wistar rats. Methylmercury chloride (6.7 mg/kg/day) was orally administrated for 5 days, followed by 2 days without administration, and this cycle was repeated once again. Seven and 14 days after the beginning of MeHg exposure, rats were anesthetized, and their DRGs and sensory and motor nerve fibers were removed and processed for immunohistochemical analyses. The frozen sections were immunostained for neuronal, Schwann cell, microglial and macrophage markers. DRG sensory neuron somata and axons showed significant degeneration on day 14. At the same time, an accumulation of microglia and the infiltration of macrophages were observed in the DRGs and sensory nerve fibers. In addition, MeHg caused significant Schwann cell proliferation in the sensory nerve fibers. In comparison, there was no noticeable change in the motor fibers. Our findings suggest that in the peripheral nervous system, MeHg toxicity is associated with neurodegenerative changes to DRG sensory neurons and the induction of a neuroprotective and/or enhancement of neurodegenerative host response.
接触有机汞,尤其是甲基汞(MeHg),会导致水俣病,这是一种严重的慢性神经紊乱疾病。水俣病主要影响中枢神经系统,因此,关于甲基汞神经毒性机制的研究主要集中在大脑。尽管外周神经系统也会受到这种有机金属化合物的影响并表现出神经退行性变的迹象,但外周甲基汞神经毒性的机制仍不清楚。在本研究中,我们对背根神经节(DRG)以及相关的感觉和运动纤维进行了定量免疫组织化学分析,以阐明甲基汞诱导的Wistar大鼠外周神经毒性的机制。每天口服氯化甲基汞(6.7毫克/千克),持续5天,然后停药2天,这个周期再重复一次。在开始接触甲基汞后的第7天和第14天,将大鼠麻醉,取出它们的背根神经节以及感觉和运动神经纤维,进行免疫组织化学分析。对冰冻切片进行神经元、施万细胞、小胶质细胞和巨噬细胞标志物的免疫染色。在第14天,背根神经节感觉神经元胞体和轴突出现明显退化。同时,在背根神经节和感觉神经纤维中观察到小胶质细胞的积聚和巨噬细胞的浸润。此外,甲基汞导致感觉神经纤维中施万细胞显著增殖。相比之下,运动纤维没有明显变化。我们的研究结果表明,在外周神经系统中,甲基汞毒性与背根神经节感觉神经元的神经退行性变化以及神经保护和/或神经退行性宿主反应增强有关。